I2‑Catalyzed Oxidative N−S Bond Formation: Metal

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Apr 27, 2017 - iodine-catalyzed oxidative cyclization of 2-aminopyridine/ami- dine and ... reactions.5a However, it is very interesting to note that iodine.
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I2‑Catalyzed Oxidative N−S Bond Formation: Metal-Free Regiospecific Synthesis of N‑Fused and 3,4-Disubstituted 5‑Imino1,2,4-thiadiazoles Nagaraju Tumula,† Nagesh Jatangi,† Radha Krishna Palakodety,† Sridhar Balasubramanian,‡ and Mangarao Nakka*,† †

Organic and Biomolecular Chemistry Division and ‡Center for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India S Supporting Information *

ABSTRACT: A novel and expeditious approach for the synthesis of N-fused and 3,4-disubstituted 5-imino-1,2,4thiadiazole derivatives has been achieved through the molecular iodine-catalyzed oxidative cyclization of 2-aminopyridine/amidine and isothiocyanate via N−S bond formation at ambient temperature. The present one-pot transition-metal-free protocol provides the facile and highly efficient regiospecific synthesis of various 1,2,4-thiadiazole derivatives in a scaled-up manner with good to excellent yields using inexpensive I2 as a catalyst.

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INTRODUCTION Nitrogen-containing heterocyclic compounds are important structures found in natural and synthetic compounds. Development of new synthetic protocols for the synthesis of biologically active N-heterocyclic compounds through various N−N, N−O, and N−S bond formations is still in high demand. As a result, a plethora of methods were developed for heteroatom− heteroatom bond formation. Among these, metal-catalyzed protocols for N−N, N−O, and N−S bond construction have limitations, such as metal contamination, drastic reaction conditions, cost factors, air sensitivity, and scalability issues.1 Earlier, metal-free protocols were developed for N−N, N−O, and N−S bond connections,2 and of all of these, iodinecatalyzed reactions played a major role owing to its environmentally friendly nature, oxidizing ability, low cost, easy availability in solid form, and easy handling. Recently, iodinecatalyzed approaches were found during C−X (X = C, N, O, S) bond formation as well as in N−N and N−S bonds.3 As a catalyst, iodine has been extensively used in organic transformations, such as esterification, acylation, and allylation as well as for Michael addition and aldol reaction.4 It can also mediate domino, iodocyclization, and one-pot multicomponent reactions.5a However, it is very interesting to note that iodine could substitute for transition metal as a catalyst.2a,5b 1,2,4-Thiadiazoles are an important class of organic molecules for medicinal chemistry and are associated with a broad range of biological activity,6a including antibacterial,6b antiulcerative,7 antidiabetic,8 antirheumatic,9 anti-inflammatory,10 and antimicrobial agents.11 A family of 1,2,4-thiadiazole derivatives also exhibits fungicidal12 and herbicidal activity.13 Despite their wide applications in pharmacology and organic synthesis, few methods were developed for the synthesis of © 2017 American Chemical Society

1,2,4-thiadiazoles. The general methods for the synthesis of 1,2,4-thiadiazoles mainly involve oxidative cyclization of primary thioamides with a variety of oxidizing reagents.14 Recently, Wehn et al. invoked a palladium-catalyzed Suzuki− Miyaura coupling reaction for ready access to 3-amino-1,2,4thiadiazoles.15a Independently, Khosropour and co-workers obtained 1,2,4-thiadiazoles from aryl nitriles in the presence of (NH4)2S and TCT−DMSO.15b On the other hand, the 1,2,4thiadiazole scaffold was also obtained from imidoyl thioureas.16 Intramolecular oxidative S−N bond formation under copper catalysis was developed by Kim et al. for ready access to 3substituted 5-amino-1,2,4-thiadiazoles.17a Muthusubramanian and co-workers developed a phenyliodine(III) bis(trifluoroacetate)-catalyzed oxidative cyclization for the synthesis of 3,5-disubstituted 1,2,4-thiadiazoles.17b However, some of these protocols suffer from limitations, such as prefunctionalization of starting materials, and require strong oxidative reaction conditions, tedious workup, and harsh reaction conditions. More importantly, these methods are mainly suitable for preparation of 3,5-disubstituted 1,2,4thiadiazoles. Thus, it is desirable to develop an efficient protocol for the synthesis of fully substituted 1,2,4-thiadiazoles using readily available raw materials in one pot. However, there seems to be no reports in the literature on I2-catalyzed N−S bond formation reactions for the synthesis of 1,2,4-thiadiazoles. Encouraged by our previous work on the development of efficient synthetic methods for various biologically active heterocycles,18 in this paper, we envisioned for the first time the construction of the N−S bond by employing molecular Received: March 20, 2017 Published: April 27, 2017 5310

DOI: 10.1021/acs.joc.7b00646 J. Org. Chem. 2017, 82, 5310−5316

Article

The Journal of Organic Chemistry

(Table 1, entry 13). Thus, the standardized conditions for this reaction are summarized as follows: 1a (3 mmol, 1 equiv), 2a (3 mmol, 1 equiv), and I2 (50 mol %) at rt in CH3CN in 1−2 h. Next, we investigated the generality of the oxidative synthesis of N-fused 1,2,4-thiadiazoles (Scheme 2). A variety of

iodine as a catalyst to synthesize the biologically important Nfused 1,2,4-thiadiazole and 3,4-disubstituted 5-imino-1,2,4thiadiazole scaffolds (Scheme 1). Scheme 1. Synthesis of N-Fused 1,2,4-Thiadiazoles and 3,4Disubstituted 5-Imino-1,2,4-thiadiazoles

Scheme 2. Synthesis of N-Fused 1,2,4-Thiadiazolesa

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RESULTS AND DISCUSSION Our initial study started with the reaction of isothiocyanate 1a with 2-aminopyridine (2a) in the presence of iodine (0.2 equiv) with no solvent (neat) at room temperature. We were delighted to observe the formation of the expected 1,2,4-thiadiazole 3a, although in low yields (Table 1, entry 1). The poor yield of 3a Table 1. Optimization of Reaction Conditionsa

entry

catalyst (mol %)

solvent

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

I2 (20) I2 (20) I2 (20) I2 (20) I2 (20) I2 (20) I2 (20) KI (20) TBAI (20) NIS (20) I2 (30) I2 (50) I2 (100)

DCE 1,4-dioxane CH3CN DMF EtOH DMSO CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

19 32 41 58 29 32 30 trace 42 36 72 91 91

a

Reaction conditions: 1a (3 mmol, 1 equiv), 2a (3 mmol, 1 equiv), I2 (50 mol %) and CH3CN (1 mL) at rt for 1−2 h. bThe reaction was conducted on gram scale.

isothiocyanates with different substituents were tested. As expected, all the isothiocyanates gave the corresponding Nfused 1,2,4-thiadiazoles in good to excellent yields. Phenyl isothiocyanate (1a) gave the desired product 3a in 91% yield. Further structural confirmation of 3a was ascertained by X-ray studies (see the Supporting Information). Arylisothiocyanates containing groups like methyl or methoxy at para-, meta-, and ortho-positions gave better reactivity and provided the corresponding products in good to excellent yields (3b, 3c, 3h, and 3i). Conversely, arylisothiocyanates with electronwithdrawing groups such as chloro and fluoro at para- and meta-positions furnished corresponding products in moderate to good yields (3d, 3e and 3j). It should be noted that arylisothiocyanates with strong electron-withdrawing groups, including −NO2 and −CF3, were well tolerated under the reaction conditions, and the desired N-fused 1,2,4-thiadiazole products were obtained in good yields (3f and 3g). It is worth mentioning that steric hindrance (3b, 3c, and 3h−3j) and electronic factors (3a−3j) of phenyl isothiocyanates seemingly

a Reaction conditions: 1a (3 mmol, 1 equiv), 2a (3 mmol, 1 equiv), catalyst (x mol %), and solvent (1 mL) at rt for 1−2 h.

might be due to the low solubility of the reactants. Next, we optimized the reaction conditions with various solvents, forward yield improvement, and the results are summarized in Table 1. Among all, acetonitrile proved to be a better solvent in terms of the reaction time and yield of the product (Table 1, entry 4). The replacement of iodine with other oxidizing catalysts, including KI, TBAI, and NIS resulted in a decrease yield of 3a (Table 1, entries 8−10). Having established the suitable catalyst for synthesis of 1,2,4-thiadiazoles, we then focused on the quantity of iodine. Increasing the loading of iodine resulted in the desired product 3a in high yields (Table 1, entries 11 and 12), and the use of 50 mol % of catalyst gave the best result (Table 1, entry 12). With further increasing of iodine from 0.5 to 1.0 equiv, the yield of 3a was not augmented 5311

DOI: 10.1021/acs.joc.7b00646 J. Org. Chem. 2017, 82, 5310−5316

Article

The Journal of Organic Chemistry Scheme 3. Synthesis of 3,4-Disubstituted 5-Imino-1,2,4-thiadiazolesa

a

Reaction conditions: 1a (1.5 mmol, 1 equiv), 2a (1.5 mmol, 1 equiv), I2 (50 mol %) and CH3CN (1 mL) at rt for 1−2 h.

exerted a negligible influence on the reaction rate or the yields of the products. An alicyclic isothiocyanate such as cyclopropyl isothiocyanate was also tolerated under these reaction conditions, and the corresponding product 3k was isolated in 79% yield. Aliphatic isothiocyanates including cyclohexyl methyl, propyl, and isopropyl underwent the oxidative reaction to give the corresponding products in good yields (3l−3n). To further examine the scope and limitations of the reaction, we studied various 2-aminopyridines with phenyl isothiocyanate (Scheme 2). Methyl-substituted 2-aminopyridine was well tolerated, and the position of the methyl substituent at 4, 5, and 6 did not bear any significant effect on the reaction yield (3o−3q). Electron-withdrawing groups such as chloro and bromo were compatiable and gave the corresponding products 3r and 3s in 87 and 86% yields, respectively. When a strong electron-withdrawing nitro group was used, the desired product 3t was obtained in 84% yield (3t). It should be noted that the catalytic transformation was successfully conducted in gram scale without any difficulty (Scheme 2, 3a). In light of a successful oxidative cyclization process for the synthesis of N-fused 1,2,4-thiadiazoles, we sought to further

extend the scope of this practical approach by replacing 2aminopyridine (2) with N-phenylbenzamidines (4) to prepare 3,4-disubstituted 5-imino-1,2,4-thiadiazoles under the optimal reaction conditions. Gratifyingly, following the above protocol, we were able to prepare 3,4-disubstituted 5-imino-1,2,4thiadiazoles very efficiently. As shown in Scheme 3, this protocol tolerates a variety of arylisothiocyanates with different N-phenylbenzamidines. No significant substituent effect was observed, and excellent yields were obtained for arylisothiocyanates having both electron-donating and electron-withdrawing substituents with different N-phenylbenzamidines. This methodology worked equally well with alicyclic isothiocyanate such as cyclopropyl, and good yield was observed (5l). Fortunately, the reaction worked equally well with aliphatic isothiocyanates, including butaryl, isopropyl, and propyl, which gave corresponding 3,4-disubstituted 5-imino1,2,4-thiadiazoles in good yields (5i, 5k, and 5m). Compound 5k was fully characterized by X-ray analysis (please see Supporting Information). To further probe the mechanism, we attempted control experiments, as shown in Scheme 4. Phenyl isothiocyanate (1a) 5312

DOI: 10.1021/acs.joc.7b00646 J. Org. Chem. 2017, 82, 5310−5316

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CONCLUSION In summary, a novel and convenient iodine-catalyzed oxidative protocol for N−S bond formation toward the regiospecific synthesis of N-fused 1,2,4-thiadiazole and 3,4-disubstituted 5imino-1,2,4-thiadiazole derivatives was developed for the first time. This versatile and transition-metal-free one-pot protocol features a broad substrate scope with inexpensive and nontoxic molecular iodine as the catalyst, and no addition of any ligand, base, or additive is need and with an easy workup procedure. The developed synthetic approach can be easily scaled up to gram scale, thereby providing the possibility for the scaled production of diverse N-fused 1,2,4-thiadiazole and 3,4disubstituted 5-imino-1,2,4-thiadiazole derivatives.

Scheme 4. Control Experiments

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EXPERIMENTAL SECTION

General Information. Unless otherwise noted, common reagents and substrates were obtained from commercial suppliers and used without further purification. 1H NMR was measured on a Bruker Avance-300, Varian Unity-400 MHz, and Avance New-500 MHz, and 13 C NMR was measured with a Varian Unity-400 MHz (100 MHz) and with Avance New-500 MHz (125 MHz), as specified and referred as the internal standard to TMS (tetramethylsilane). High-resolution mass spectra (HRMS) were performed on a high-resolution magnetic sector mass spectrometer. Melting points were recorded on a Büchi 535 melting point apparatus and are uncorrected. TLC analysis was performed on Merck silica gel 60 F254 plates. Column chromatography was performed on silica gel (100−200 mesh) from Merck. Typical Procedure for the Synthesis of N-Fused 1,2,4Thiadiazoles 3a−3t. A mixture comprised isothiocyanate (1) (3 mmol), 2-aminopyridine (2) (3 mmol), and I2 (50 mol %, 202 mg, 1.5 mmol) in CH3CN (1 mL) at room temperature. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with a saturated aqueous solution of Na2S2O3. The organic and aqueous layers were then separated, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude. The crude was purified by silica gel column chromatography using EtOAc/hexane as eluents to afford corresponding product 3. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3a): 20 Yield 91% (659 mg); pale yellow solid; mp 124−126 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (500 MHz, CDCl3) δ = 8.21 (d, J = 7.17 Hz, 1H), 7.42−7.37 (m, 2H), 7.22−7.10 (m, 4H), 7.06−7.03 (m, 1H), 6.46 (dd, J = 0.92 Hz, J = 5.34 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ = 159.2, 151.6, 148.5, 133.4, 129.5, 126.1, 124.3, 121.1, 119.4, 109.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H10N3S 228.0512; found 228.0520. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-methylaniline (3b): 21 Yield 90% (692 mg); pale yellow solid; mp 104−106 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (500 MHz, CDCl3) δ = 8.20 (d, J = 7.17 Hz, 1H), 7.21−7.16 (m, 3H), 7.07−7.02 (m, 3H), 6.46−6.42 (m, 1H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 158.5, 151.6, 145.9, 133.8, 133.3, 130.1, 126.1, 120.9, 119.4, 109.5, 21.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12N3S 242.0745; found 242.0746. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-methoxyaniline (3c): 22 Yield 95% (779 mg); pale yellow solid; mp 125−127 °C; eluent, hexane/ethyl acetate 94:6; 1H NMR (400 MHz, CDCl3) δ

with 2-aminopyridine (2a) under optimized conditions in inert atmosphere gave the desired 3a in 91% (Scheme 4a). It is highly likely that I2 plays the role of oxidant. As expected, when 2,2,6,6-tetramethylpiperdine-1-oxide (TEMPO, a well-known radical inhibitor) was added to the reaction, no considerable effect was observed (Scheme 4b), demonstrating that a radical mechanism was ruled out. When the phenyl isothiocyanate (1c) was reacted with 2-aminopyridine (2a) in the absence of I2, intermediate C′ (Scheme 4c) was obtained, which was confirmed by 1H, 13C NMR, HRMS, and X-ray analysis (see the Supporting Information). However, C′ did not produce 3c′ in the presence of I2 (Scheme 4d). Thus, it maybe deduced that the present protocol is highly regiospecific and affords 3c exclusively. Based on the results presented above and previous reports,19 a plausible mechanism was proposed and shown in Scheme 5. The first step for the formation of product 3a involves a nucleophilic attack of activated 2-aminopyridine (A) on phenyl isothiocyanate (1a) to form intermediate B. Finally, the intermolecular nucleophilic attack of the NH group on the sulfur atom gave the corresponding derivative 3a. However, when the same reaction was performed in the absence of I2, nucleophilic addition of free amine on isothiocyanate gave stable thiourea derivative C′, which was isolated and characterized by its 1H, 13C NMR, HRMS, as well as X-ray analysis. Independently, C′ upon treatment with I2 did not afford the cyclized regioisomer 3c′ (Scheme 4d). Thus, it conclusively proves the intermediacy of B and its conversion into product 3a. Scheme 5. Plausible Mechanism for the Preparation of 3a

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DOI: 10.1021/acs.joc.7b00646 J. Org. Chem. 2017, 82, 5310−5316

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The Journal of Organic Chemistry

2H); 13C{1H} NMR (100 MHz, CDCl3) δ = 161.4, 152.2, 133.2, 125.7, 119.3, 108.9, 36.0, 7.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C9H10N3S 192.0543; found 192.0551. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-1-cyclohexylmethanamine (3l): Yield 78% (614 mg); pale yellow liquid; eluent, hexane/ethyl acetate 90:10; 1H NMR (500 MHz, CDCl3) δ = 7.95 (d, J = 7.17 Hz 1H), 7.13−7.09 (m, 1H), 6.94 (d, J = 9.46 Hz, 1H), 6.32 (t, J = 7.02 Hz, 1H), 2.96 (d, J = 6.56 Hz, 2H), 1.87−1.80 (m, 2H), 1.78−1.64 (m, 4H), 1.33−1.26 (m, 2H), 1.23−1.16 (m, 1H), 1.08− 0.96 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ = 158.3, 152.3, 133.3, 126.1, 119.3, 108.6, 61.7, 39.4, 31.5, 26.6, 26.1; HRMS (ESITOF) m/z [M + H]+ calcd for C13H18N3S 248.1208; found 248.1215. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)propan-1amine (3m): Yield 76% (468 mg); pale yellow liquid; eluent, hexane/ ethyl acetate 90:10; 1H NMR (300 MHz, CDCl3) δ = 7.98−7.94 (m, 1H), 7.16−7.09 (m, 1H), 6.98−6.93 (m, 1H), 6.37−6.31 (m, 1H), 3.11 (t, J = 6.87 Hz, 2H), 1.82−1.68 (m, 2H), 1.01 (t, J = 7.43 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ = 158.6, 152.3, 133.3, 126.0, 119.3, 108.7, 56.7, 23.9, 12.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C9H12N3S 194.0756; found 194.0759. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)propan-2amine (3n): Yield 76% (468 mg); pale yellow liquid; eluent, hexane/ ethyl acetate 90:10; 1H NMR (500 MHz, CDCl3) δ = 7.94 (d, J = 7.32 Hz, 1H), 7.13−7.08 (m, 1H), 6.92 (d, J = 9.46 Hz, 1H), 6.31 (t, J = 7.02 Hz, 1H), 3.19−3.10 (m, 1H), 1.24 (d, J = 6.26 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ = 157.1, 152.3, 133.3, 126.2, 119.2, 108.6, 56.4, 22.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C9H12N3S 194.0745; found 194.0746. (Z)-N-(7-Methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3o): Yield 86% (575 mg); pale yellow solid; mp 104−106 °C; eluent, hexane/ethyl acetate 93:7; 1H NMR (400 MHz, CDCl3) δ = 8.11 (d, J = 7.34 Hz, 1H), 7.41−7.36 (m, 2H), 7.16−7.08 (m, 3H), 6.82−6.79 (m, 1H), 6.30 (dd, J = 1.46 Hz, J = 7.34 Hz, 1H), 2.26 (d, J = 1.22 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ = 159.3, 151.8, 148.6, 144.8, 129.5, 124.9, 124.2, 121.1, 116.8, 112.8, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12N3S 242.0756; found 242.0759. (Z)-N-(6-Methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3p): Yield 86% (575 mg); pale yellow solid; mp 147−149 °C; eluent, hexane/ethyl acetate 94:6; 1H NMR (500 MHz, CDCl3) δ = 8.00 (s, 1H), 7.39 (t, J = 7.78 Hz, 2H), 7.18−7.05 (m, 4H), 7.01−6.97 (m, 1H), 2.22 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ = 159.5, 151.2, 148.7, 136.8, 129.5, 124.1, 122.7, 121.1, 119.4, 118.6, 17.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12N3S 242.0767; found 242.0773. (Z)-N-(5-Methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3q): Yield 86% (575 mg); pale yellow solid; mp 98−100 °C; eluent, hexane/ethyl acetate 93:7; 1H NMR (500 MHz, CDCl3) δ = 7.38 (t, J = 7.78 Hz, 2H), 7.11 (t, J = 7.47 Hz, 1H), 7.04 (d, J = 7.47 Hz, 2H), 6.90 (dd, J = 6.56 Hz, J = 9.46 Hz, 1H), 6.79 (d, J = 9.31 Hz, 1H), 5.99 (d, J = 6.56 Hz, 1H), 2.96 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ = 163.0, 154.0, 150.2, 141.9, 132.6, 129.7, 124.2, 120.3, 118.1, 110.7, 21.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12N3S 242.0753; found 242.0758. (Z)-N-(8-Chloro-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3r): Yield 87% (532 mg); pale yellow solid; mp 136−138 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (500 MHz, CDCl3) δ = 8.20 (dd, J = 1.06 Hz, J = 7.17 Hz, 1H), 7.42−7.38 (m, 2H), 7.34 (dd, J = 1.06 Hz, J = 7.02 Hz, 1H), 7.16−7.11 (m, 3H), 6.43 (t, J = 7.02 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ = 158.9, 148.4, 147.9, 131.9, 129.6, 125.1, 124.8, 124.6, 121.0, 109.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H9ClN3S 262.0145; found 262.0149. (Z)-N-(6-Bromo-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3s): Yield 86% (456 mg); pale yellow solid; mp 147−149 °C; eluent, hexane/ethyl acetate 92:8; 1H NMR (500 MHz, CDCl3) δ = 8.37 (dd, J = 0.85 Hz, J = 1.95 Hz, 1H), 7.43−7.37 (m, 2H), 7.21 (dd, J = 1.98 Hz, J = 9.76 Hz, 1H), 7.16−7.10 (m, 3H), 6.95 (dd, J = 0.76 Hz, J = 9.92 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ = 157.6, 149.6, 147.9, 136.7, 129.6, 125.8, 124.5, 121.0, 119.9, 104.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H9BrN3S 305.9691; found 305.9695.

= 8.20 (d, J = 7.21 Hz, 1H), 7.21−7.16 (m, 1H), 7.11−7.06 (m, 2H), 7.05−7.01 (m, 1H), 6.96−6.91 (m, 2H), 6.44 (dd, J = 5.38 Hz, J = 0.97 Hz, 1H), 3.82 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ = 157.9, 156.3, 151.6, 141.6, 133.4, 126.1, 122.2, 119.4, 114.7, 109.5, 55.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12N3OS 258.0654; found 258.0663. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-chloroaniline (3d): 22 Yield 88% (733 mg); pale yellow solid; mp 144−146 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ = 8.19 (d, J = 7.17 Hz, 1H), 7.36−7.32, (m, 2H), 7.24−7.20 (m, 1H), 7.09−7.06 (m, 3H), 6.49 (dd, J = 1.06 Hz, J = 5.34 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ = 159.7, 151.6, 147.1, 133.4, 129.6, 129.1, 125.9, 122.4, 119.4, 109.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H9ClN3S 262.0137; found 262.0142. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-fluoroaniline (3e): 22 Yield 88% (688 mg); pale yellow solid; mp 148−150 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ = 8.19 (d, J = 7.17 Hz, 1H), 7.23−7.19 (m, 1H), 7.12−7.05 (m, 5H), 6.48 (dd, J = 1.06 Hz, J = 5.34 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ = 159.9 (d, J = 102 Hz), 158.5, 151.6, 144.7, 133.4, 125.9, 122.4 (d, J = 7 Hz), 119.4, 116.2 (d, J = 18 Hz), 109.7; HRMS (ESITOF) m/z [M + H]+ calcd for C12H9FN3S 246.0493; found 246.0495. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-nitroaniline (3f): 22 Yield 85% (737 mg); orange solid; mp 189−191 °C; eluent, hexane/ethyl acetate 92:8; 1H NMR (400 MHz, CDCl3) δ = 8.30−8.25 (m, 3H), 7.33−7.28 (m, 1H), 7.26−7.22 (m, 2H), 7.19− 7.15 (m, 1H), 6.63−6.58 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ = 161.7, 154.3, 151.6, 143.5, 133.6, 125.8, 125.5, 121.5, 119.5, 110.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H9N4O2S 273.0435; found 273.0441. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4(trifluoromethyl)aniline (3g): Yield 82% (772 mg); pale yellow solid; mp 158−160 °C; eluent, hexane/ethyl acetate 93:7; 1H NMR (500 MHz, CDCl3) δ = 8.24−8.20 (m, 1H), 7.64 (d, J = 8.55 Hz, 2H), 7.27−7.20 (m, 3H), 7.13−7.08 (m, 1H), 6.55−6.50 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ = 158.2, 149.1, 130.9, 125.0, 124.2 (d, J = 2 Hz), 123.4, 123.3 (q, J = 48.1 Hz), 121.8 (d, J = 216 Hz), 118.7, 116.9, 107.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H9F3N3S 296.0460; found 296.0464. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-3-methylaniline (3h): Yield 82% (631 mg); pale yellow liquid; eluent, hexane/ ethyl acetate 95:5; 1H NMR (500 MHz, CDCl3) δ = 8.23−8.19 (m, 1H), 7.30−7.25 (m, 1H), 7.20 (dd, J = 1.37 Hz, J = 5.04 Hz, 1H), 7.07−7.03 (m, 1H), 6.98−6.92 (m, 3H), 6.49−6.44 (m, 1H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 159.0, 151.6, 148.5, 139.5, 133.3, 129.4, 126.1, 125.1, 121.9, 119.4, 117.7, 109.6, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12N3S 242.0745; found 242.0746. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-2-methoxyaniline (3i): Yield 82% (672 mg); pale yellow liquid; eluent, hexane/ ethyl acetate 91:9; 1H NMR (500 MHz, CDCl3) δ = 8.26−8.23 (m, 1H), 7.19 (dd, J = 1.37 Hz, J = 5.04 Hz, 1H), 7.14−7.09 (m, 2H), 7.03 (d, J = 9.46 Hz, 1H), 7.00−6.96 (m, 2H), 6.48−6.44 (m, 1H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 160.4, 151.6, 151.4, 138.1, 133.1, 126.2, 125.3, 121.3, 120.6, 119.4, 112.0, 109.6, 55.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12N3OS 258.0694; found 258.0695. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-3-chloroaniline (3j): Yield 86% (716 mg); pale yellow solid; mp 107−109 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (500 MHz, CDCl3) δ = 8.20−8.17 (m, 1H), 7.30 (t, J = 7.93 Hz, 1H), 7.22 (dd, J = 1.37 Hz, J = 5.04 Hz, 1H), 7.14 (t, J = 1.98 Hz, 1H), 7.11−7.05 (m, 2H), 7.02 (dd, J = 1.37 Hz, J = 8.08 Hz, 1H), 6.51−6.47 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ = 160.2, 151.5, 149.8, 135.0, 133.4, 130.5, 125.9, 124.2, 121.7, 119.4, 119.1, 110.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H9ClN3S 262.0154; found 262.0159. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)cyclopropanamine (3k): Yield 79% (481 mg); pale yellow liquid; eluent, hexane/ethyl acetate 90:10; 1H NMR (400 MHz, CDCl3) δ = 7.90−7.86 (m, 1H), 7.15−7.10 (m, 1H), 6.99−6.95 (m, 1H), 6.35− 6.31 (m, 1H), 2.49−2.42 (m, 1H), 0.86−0.83 (m, 2H), 0.69−0.65 (m, 5314

DOI: 10.1021/acs.joc.7b00646 J. Org. Chem. 2017, 82, 5310−5316

Article

The Journal of Organic Chemistry (Z)-N-(6-Nitro-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3t): Yield 84% (493 mg); orange solid; mp 180−182 °C; eluent, hexane/ethyl acetate 91:9; 1H NMR (500 MHz, CDCl3) δ = 9.38−9.35 (m, 1H), 7.91 (dd, J = 2.32 Hz, J = 10.27 Hz, 1H), 7.46− 7.41 (m, 2H), 7.20 (t, J = 7.46 Hz, 1H), 7.16−7.13 (m, 2H), 7.08 (d, J = 10.27 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ = 155.8, 149.2, 146.7, 135.1, 129.7, 127.9, 126.9, 125.5, 121.1, 119.3; HRMS (ESITOF) m/z [M + H]+ calcd for C12H9N4O2S 273.0451; found 273.0458. Typical Procedure for the Synthesis of 3,4-Disubstituted 5Imino-1,2,4-thiadiazoles 5a−5m. A mixture comprised isothiocyanate (1) (1.5 mmol), N-phenylbenzamidines (4) (1.5 mmol), and I2 (50 mol %, 97 mg, 0.75 mmol) in CH3CN (1 mL) at room temperature for 1−2 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with a saturated aqueous solution of Na2S2O3. The organic and aqueous layers were then separated, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude. The crude was purified by silica gel column chromatography using EtOAc/hexane as eluents to afford corresponding product 5. (Z)-N-(3,4-Diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)aniline (5a): 23 Yield 89% (448 mg); white solid; mp 196−198 °C; eluent, hexane/ ethyl acetate 95:5; 1H NMR (500 MHz, CDCl3) δ = 1H NMR (400 MHz, CDCl3) δ 7.44−7.27 (m, 10H), 7.26−7.19 (m, 2H), 7.10−6.99 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 164.5, 157.1, 150.6, 136.6, 130.3, 130.1, 129.53, 129.47, 128.8, 128.6, 128.3, 124.0, 121.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H16N3S 330.1034; found 330.1037. (Z)-N-(3,4-Diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-4-methylaniline (5b): Yield 90% (472 mg); white solid; mp 192−194 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (500 MHz, CDCl3) δ = 7.42− 7.27 (m, 8H), 7.25−7.21 (m, 2H), 7.12 (d, J = 8.08 Hz, 2H), 6.91 (d, J = 8.24 Hz, 2H), 2.31 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ = 164.1, 157.1, 148.2, 136.6, 133.4, 130.2, 130.15, 130.06, 129.4, 128.76, 128.72, 128.6, 128.3, 120.7, 20.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H18N3S 344.1209; found 344.1215. (Z)-N-(3,4-Diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-4-methoxyaniline (5c): Yield 90% (494 mg); white solid; mp 207−209 °C; eluent, hexane/ethyl acetate 94:6; 1H NMR (500 MHz, CDCl3) δ = 7.43− 7.26 (m, 8H), 7.25−7.20 (m, 2H), 6.98−6.93 (m, 2H), 6.89−6.83 (m, 2H), 3.79 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ = 164.0, 157.1, 156.2, 144.1, 136.7, 130.3, 130.1, 129.4, 128.76, 128.72, 128.6, 128.3, 121.9, 114.6, 55.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H18N3OS 360.1161; found 360.1165. (Z)-4-Chloro-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)aniline (5d): Yield 87% (483 mg); white solid; mp 170−172 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ = 7.44−7.21 (m, 12H), 6.98−6.92 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ = 164.9, 157.2, 149.3, 136.5, 130.4, 129.9, 129.55, 129.48, 128.9, 128.7, 128.6, 128.3, 122.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H15ClN3S 364.0641; found 364.0645. (Z)-N-(3,4-Diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-4-nitroaniline (5e): Yield 86% (492 mg); pale yellow solid; mp 180−182 °C; eluent, hexane/ethyl acetate 93:7; 1H NMR (300 MHz, CDCl3) δ = 8.20(d, J = 9.07 Hz, 2H), 7.48−7.23 (m, 10H), 7.12 (d, J = 9.07 Hz, 2H); 13 C{1H} NMR (125 MHz, CDCl3) δ = 166.2, 157.4, 156.4, 143.6, 136.2, 130.6, 129.6, 129.5, 129.3, 128.8, 128.5, 128.4, 125.5, 121.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H15N4O2S 375.0838; found 375.0842. (Z)-N-(3,4-Diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-4(trifluoromethyl)aniline (5f): Yield 82% (528 mg); white solid; mp 227−229 °C; eluent, hexane/ethyl acetate 94:6; 1H NMR (300 MHz, CDCl3) δ = 7.57 (d, J = 8.53 Hz, 2H), 7.47−7.22 (m, 10H), 7.10 (d, J = 8.53 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ = 165.5, 157.2, 153.7, 136.4, 130.5, 129.7, 129.5, 129.0, 128.7, 128.6, 128.3, 126.7 (d, J = 3 Hz), 125.7 (d, J = 26 Hz), 123.3, 121.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H15F3N3S 398.0929; found 398.0933. (Z)-N-(3,4-Diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-2-methoxyaniline (5g): Yield 82% (450 mg); white solid; mp 132−134 °C; eluent, hexane/ethyl acetate 94:6; 1H NMR (500 MHz, CDCl3) δ = 7.42 (m,

2H), 7.36−7.27 (m, 6H), 7.26−7.20 (m, 2H), 7.08−7.03 (m, 1H), 6.99−6.95 (m, 1H), 6.93−6.88 (m, 2H), 3.80 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ = 165.1, 156.9, 151.1, 140.1, 136.6, 130.2, 130.1, 129.4, 128.76, 128.70, 128.6, 128.2, 124.9, 121.5, 121.3, 112.4, 55.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H18N3OS 360.1157; found 360.1162. (Z)-3-Chloro-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)aniline (5h): Yield 87% (483 mg); white solid; mp 164−166 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ = 7.45−7.20 (m, 11H), 7.06−7.01 (m, 2H), 6.94−6.89 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ = 165.3, 157.2, 151.8, 136.4, 134.9, 130.5, 130.4, 129.8, 129.5, 128.9, 128.7, 128.6, 128.3, 123.9, 121.6, 119.0; HRMS (ESI-TOF) m/z [M + H] + calcd for C20H15ClN3S 364.0669; found 364.0669. (Z)-N-(3,4-Diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)butan-1amine (5i): Yield 74%(349 mg); white solid; mp 120−122 °C; eluent, hexane/ethyl acetate 92:8; 1H NMR (300 MHz, CDCl3) δ = 7.40− 7.14 (m, 10H), 3.11 (t, J = 7.15 Hz, 2H), 1.66−1.54 (m, 2H), 1.44− 1.30 (m, 2H), 0.92 (t, J = 7.43 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 162.4, 157.5, 136.7, 130.4, 130.1, 129.3, 128.7, 128.6, 128.5, 128.2, 55.6, 32.4, 20.6, 14.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H20N3S 310.1362; found 310.1367. (Z)-N-(4-Phenyl-3-(p-tolyl)-1,2,4-thiadiazol-5(4H)-ylidene)aniline (5j): Yield 76% (372 mg); white solid; mp 175−177 °C; eluent, hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3) δ = 7.45− 7.27 (m, 7H), 7.21−7.16 (m, 2H), 7.09−6.99 (m, 5H), 2.30 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ = 164.5, 157.2, 150.7, 143.0, 140.6, 136.7, 129.5, 129.4, 128.9, 128.62, 128.67, 127.2, 123.9, 121.0, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H18N3S 344.1221; found 344.1224. (Z)-N-(4-Phenyl-3-(p-tolyl)-1,2,4-thiadiazol-5(4H)-ylidene)propan-2-amine (5k): Yield 75% (331 mg); white solid; mp 164−166 °C; eluent, hexane/ethyl acetate 92:8; 1H NMR (400 MHz, CDCl3) δ = 7.36−7.26 (m, 3H), 7.18−7.10 (m, 4H), 7.00 (d, J = 8.06 Hz, 2H), 3.08−2.98 (m, 1H), 2.27 (s, 3H), 1.14 (d, J = 6.23 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ = 160.1, 157.5, 140.2, 137.1, 129.1, 128.8, 128.7, 128.6, 128.1, 127.7, 57.4, 23.2, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H20N3S 310.1332; found 310.1336. (Z)-N-(4-Phenyl-3-(p-tolyl)-1,2,4-thiadiazol-5(4H)-ylidene)cyclopropanamine (5l): Yield 76% (333 mg); white solid; mp 166− 168 °C; eluent, hexane/ethyl acetate 91:9; 1H NMR (500 MHz, CDCl3): δ = 7.36−7.28 (m, 3H), 7.16−7.12 (m, 4H), 7.01 (d, J = 8.08 Hz, 2H), 2.45−2.39 (m, 1H), 2.28 (s, 3H), 0.75−0.70 (m, 2H), 0.57− 0.53 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ = 166.4, 157.6, 140.4, 136.7, 129.3, 128.8, 128.62, 128.58, 128.4, 127.5, 36.3, 21.4, 7.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H18N3S 308.1124; found 308.1131. (Z)-N-(4-Phenyl-3-propyl-1,2,4-thiadiazol-5(4H)-ylidene)propan1-amine (5m): Yield 73% (352 mg); liquid; eluent, hexane/ethyl acetate 90:10; 1H NMR (500 MHz, CDCl3) δ = 7.54−7.48 (m, 2H), 7.47−7.41 (m, 1H), 7.28−7.23 (m, 2H), 3.00 (t, J = 7.02 Hz, 2H), 2.24 (t, J = 7.47 Hz, 2H), 1.65−1.53 (m, 4H), 0.89−0.85 (m, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ = 163.1, 159.0, 136.3, 129.9, 129.1, 128.6, 57.8, 32.8, 23.5, 19.1, 13.6, 11.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H20N3S 262.1367; found 262.1372.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00646. Copies of 1H and 13C NMR spectral data for all products (PDF) X-ray crystallographic data for 3a (CIF) X-ray crystallographic data for 5k (CIF) X-ray crystallographic data for C′ (CIF) 5315

DOI: 10.1021/acs.joc.7b00646 J. Org. Chem. 2017, 82, 5310−5316

Article

The Journal of Organic Chemistry

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Mangarao Nakka: 0000-0003-1882-1117 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge SERB, New Delhi, India (PDF/ 2016/000177), for financial support in the form of NPDF. The authors T.N. and J.N. thank the CSIR and UGC, New Delhi, for financial support in the form of fellowships.

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DOI: 10.1021/acs.joc.7b00646 J. Org. Chem. 2017, 82, 5310−5316